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Adolescent administration of Δ9-THC decreases the expression and function of muscarinic-1 receptors in prelimbic prefrontal cortical neurons of adult male mice.

TitleAdolescent administration of Δ9-THC decreases the expression and function of muscarinic-1 receptors in prelimbic prefrontal cortical neurons of adult male mice.
Publication TypeJournal Article
Year of Publication2021
AuthorsGarzón M, Wang G, Chan J, Bourie F, Mackie K, Pickel VM
JournalIBRO Neurosci Rep
Volume11
Pagination144-155
Date Published2021 Dec
ISSN2667-2421
Abstract

Long-term cannabis use during adolescence has deleterious effects in brain that are largely ascribed to the activation of cannabinoid-1 receptors (CB1Rs) by delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive compound in marijuana. Systemic administration of ∆9-THC inhibits acetylcholine release in the prelimbic-prefrontal cortex (PL-PFC). In turn, PL-PFC acetylcholine plays a role in executive activities regulated by CB1R-targeting endocannabinoids, which are generated by cholinergic stimulation of muscarinic-1 receptors (M1Rs). However, the long-term effects of chronic administration of increasing doses of ∆9-THC in adolescent males on the distribution and function of M1 and/or CB1 receptors in the PL-PFC remains unresolved. We used C57BL\6J male mice pre-treated with vehicle or escalating daily doses of ∆9-THC to begin filling this gap. Electron microscopic immunolabeling showed M1R-immunogold particles on plasma membranes and in association with cytoplasmic membranes in varying sized dendrites and dendritic spines. These dendritic profiles received synaptic inputs from unlabeled, CB1R- and/or M1R-labeled axon terminals in the PL-PFC of both treatment groups. However, there was a size-dependent decrease in total (plasmalemmal and cytoplasmic) M1R gold particles in small dendrites within the PL-PFC of mice receiving ∆9-THC. Whole cell current-clamp recording in PL-PFC slice preparations further revealed that adolescent pretreatment with ∆9-THC attenuates the hyperpolarization and increases the firing rate produced by local muscarinic stimulation. Repeated administration of ∆9-THC during adolescence also reduced spontaneous alternations in a Y-maze paradigm designed for measures of PFC-dependent memory function in adult mice. Our results provide new information implicating M1Rs in cortical dysfunctions resulting from adolescent abuse of marijuana.

DOI10.1016/j.ibneur.2021.09.005
Alternate JournalIBRO Neurosci Rep
PubMed ID34667972
PubMed Central IDPMC8506972